Barbituric acid compound



Patented May 14, 1940 NlTED STATES PATENT OFFICE BARBITURIC ACIDCOMPOUND William G. Bywater, Detroit, Mich., assignor to Parke, Davis &Company, Detroit, Mich., a corporation of Michigan No Drawing.Application February 2, 1938, Serial No. 188,396

13 Claims.

The invention relates to new barbiturates, that is, barbituric acids andtheir salts, and more particularly to barbiturates having twohydrocarbon radicals attached to the 5-carbon atom of the barbituricacid ring, at least one of which hydrocarbonradicals is an isopropenylalkyl carbinyl radical.

The general formula for the compounds of the invention may be written asfollows,

as cyclopentenyl or cyclohexenyl; aryl, such as phenyl, etc.

From the above definition of R, it will be seen that the compounds ofthe invention are secondary alkyl substituted barbiturates where thesecondary alkyl radical,

CH3 R contains at least five and not more than ten carbon atoms.

In carrying out the invention, one may use any of the known methods forforming barbituric acid where R has the same significance as given inthe previous formulas, and react the halide either with an alkalicompound of a malonic ester of formula, 1

M COORs or with the corresponding barbituric acid compound of formula, 1

where R1 has the significance already given above, R3 and R4 are alkylradicals,'and M represents an alkali metal such as sodium.

When the halide reacts with the alkali compound of the malonic ester adi-substituted malonic ester of formula, Y CH 0GH is obtained. Thismalonic ester can then be re.-

GOORs OOOR4 acted in known manner with urea to form the new barbituricacids of the invention. The acids are readily converted by reaction withbasic or alkaline salt-forming compounds into their correspondingbarbituric acid salts, included in the general formula given above.

When the halide reacts with the alkali compound of the mono-substitutedbarbituric acid, the di-substituted barbituric acid of the invention isdirectly produced.

Instead of carryingout the above described reaction between the halide,III, and the alkali metal compound, V, the same barbituric acidcompounds can be prepared by reacting the halide, III, with an alkalicompound of an unsubstituted malonic ester of formula,

11 \COOBA VII to form the corresponding mono-substituted malonic esterhaving the isopropenyl alkyl carbinyl radical attached to the methylenecarbon atom. The mono-substituted ester can then be converted into itsalkali metal compound and reacted with an alkyl halide, Rl-l-Ial, whereR1 is a hydrocarbon radical containing not more than six carbon atoms asalready described. The latter reaction results in the di-substitutedmalonic ester, VI, described above and which is then converted into abarbituric acid by reaction with urea. Likewise, the halide R1-I-Ial canbe reacted with an alkali metal compound of an isopropenyl alkylcarbinyl barbituric acid of formula,

where R is a hydrocarbon radical containing not more than six carbonatoms, to directly form the new barbituric acids of the invention.

The invention can also be carried out by reacting the halide, R1-Ha-l,as given above, or the isopropenyl alkyl carbinyl halide, III, withcyanoacetic ester by the known methods to obtain, respectively,mono-substituted cyanoacetic esters,

CH3 R H 0003s (I: l

or CH2= CH COOR; /o R1 GEN IX X Either of the compounds, IX and X, canthen be reacted with alkali metal to replace the methylene hydrogen atomby alkali metal and the resulting compounds reacted with the halide, III(in the case of IX), or with the halide, R1-Hal (in the case of X), togive a di-hydrocarbon substituted cyanoacetic ester of formula,

This di-substituted ester is then reacted in the known manner with analkali alcoholate and a suitable urea compound, such as urea orguanidine, to give an imino barbituric acid compound such as,

The imino compound can be hydrolyzed, for example, by using a solutionof a strong mineral acid such as hydrochloric acid. The hydrolysisgenerates the desired barbituric acid of the formula given above.

The compounds of the invention are useful not only because theyconstitute a new group of chemical substances having special propertiesby virtue of the kind of hydrocarbon groups substituted at the methylenecarbon atom of the barbituric acid ring, but are also valuablepharmaceutically, especially as soporifics and hypnotics.

It has been found that barbiturates having an ethylenic hydrocarbonradical attached to the barbituric acid methylene carbon atom are proneto produce a convulsant action when administered to the animal organism.On the other hand, the compounds of the present invention are remarkablyfree from such convulsant action and this is believed to be due to thepresence of the isopropenyl group, as well as to the fact that thesubstituting radical containing the isopropenyl group is a secondaryalkyl radical.

Although the invention includes preparation of a large class of chemicalcompounds, I have found that the preferred compounds from the standpointof hypnotic. properties, which are low in toxicity and lacking in otherundesirable physiological properties, but high in effectiveness ashypnotics and soporifics, are those in which R1 of the general formula,I, is a member of the group ethyl and allyl.

The invention may be illustrated by the following examples.

EXAMPLE 1.Preparation of isop'ropenylethylcarbinol Ethyl magnesiumbromide is first prepared in the usual manner (Organic Syntheses 2H, 98,John Wiley liz Sons, Inc., 1931). 52.8 grams (2.2 moles) of magnesiumturnings are covered with 500 cc. of anhydrous ether. added 20 cc. ofethyl bromide and a crystal of iodine. After the reaction has started,the remainder of the ethyl bromide (total of 238 grams or 2.2 moles) in300 cc. of anhydrous ether is added to the reaction vessel while thereaction mixture is stirred vigorously and the vessel cooled in anice-bath. When all the ethyl bromide has been added the reaction mixtureis heated for one-half hour at roomtemperature. The ether solution atthis point is dark colored and has in it a slight grey precipitate. Toit is added dropwise, while stirring and cooling in an ice-bath, grams(2 moles) of methylacrolein in 200 cc. of ether. The reaction mixture isstirred for onehalf hour after the methylacrolein has been added. All ofthe Grignard reagent is used up as shown by the Gilman color 'test(Gilman and Schultz, J. Am. Chem. Soc. 4'7, 2002 (1925) The reactionmixture is-allowed' to stand for. 15 to 18 hours then the product ishydrolyzed by first adding cold wateruntil the first vigorous reactionhas subsided, thenneutralizing the mixture with 2.2 equivalents ofhydrochloric aciddiluted with ice. 'The grey solid in the flask slowlydissolves. The ether layeris separated in a large separatory funnel, andthe aqueous phase extracted with 250 cc. of ether. The extract is addedto the original ether solution and dried over powdered lime, filteredand fractionated. The fraction boiling at 129-134 at 753 mm. iscollected. The index of refraction is and the yield is 58.2 percentbased on the methylacrolein used.

The reactions used in the above example may be represented as follows:

(1113 (EH: CHz' C-CHO-f-CzHsMEBI ClipC-CHCHgCH;

OMgBr CH3 H2 27 UHF -OHCH1CHI (RC1) H To the flask is then EXAMPLE zPre'paratz'on of isopropenylethylcarbinyl chloride 160 grams (1.6 moles)of isopropenylethylcarbinol and 193 grams (1.6 moles) of dimethylanilineare mixed in a one-liter three-necked flask equipped with a mechanicalstirrer, dropping funnel and thermometer. The flask and contents arecooled in an ice-bath and while the solution is stirred vigorously, 190grams of thionyl chloride is slowly added through the dropping funnel.The temperature of the reaction mixture does not rise above that of theroom. When all the thionyl chloride has been added, the reaction mixtureis stirred for two hours at room temperature then transferred to aseparatory funnel and the lower dark layer removed. The upper layer iswashed first with cold Water, then with 25 cc. of 5 percent hydrochloricacid, finally with 50 cc. of 10 percent sodium carbonate solution anddried with anhydrous calcium chloride. The crudeisopropenylethylcarbinyl chloride is first fractionated under reducedpressure then finally distilled at atmospheric pressure. The chloride isa colorless liquid possessing a strong characteristic odor. It rapidlyattacks rubber and cork stoppers and is best handled in all-glassapparatus. It boils at 121-124" 0.;

EXAMPLE 3.Prepamtion of ethyl ethyl- (isopropenylethylcarbinyl) malonateA sodium ethylate solution is prepared from 4.6 grams (0.20 moles) offreshly cut metallic sodium and 70.5 cc. of absolute ethyl alcohol towhich is added 38.1 grams (0.20 moles) of ethyl ethylmalonate. Thetemperature of solution is adjusted to about 40 C. and the addition ofisopropenylethylcarbinyl chloride started. As salt begins to separatefrom the solution the temperature rises. The chloride is added in smallportions, with shaking after each portion. When i all the chloride hasbeen introduced into the flask, the mixture is allowed to stand forfifteen minutes at room temperature, then it is gently heated at -110",at the same time removing half of the alcohol by distillation. Thedesired ester is isolated by first adding sufficient water to thereaction mixture to dissolve the precipitated sodium chloride, and thenseparating the aqueous and oily layers. The aqueous layer is extractedwith a small quantity of ether which is added to the main portion ofester. The oil, after drying with anhydrous calcium chloride, isfractionated under reduced pressure. Ethylisopropenylethylcarbinylethylmalonate is a colorless liquid possessing apleasant fruity odor. It distills at l1'7.5-1l9 at about 3.5 mm.pressure;

The reactions in this example may be represented as follows:

EXAMPLE 4.-Preparation of ethyl isopropenylethylcarbinyl barbituric:acid To a solution of sodium ethylate prepared from 4 grams of sodiumand 63 cc. of anhydrous ethyl alcohol there is added 16.5 grams (0.06mole) of ethyl ethylisopropenylethylcarbinyl malonate and 5.4 grams (.09mole) of urea. The solution is then concentrated by distilling 38 cc. ofalcohol from thereaction flask. It is then gently refluxed in an oilbath. The total time consumed for these two operations is 3 hours. Thereaction mixture is diluted with water and the alkaline solutionfiltered until clear. Dilute hydrochloric acid is then used toprecipitate ethyl isopropenylethylcarbinyl barbituric acid as a whitecrystalline solid which, after several recrystallizations from alcohol,melts at 146-147.5.

The barbituric acid in this example has the EXAMPLE 5. -P'repamtion ofsalts of ethyl 2'80 propenylethylcarbmyl barbituric acid A solutioncontaining a mole of alkali metal hydroxide or alcoholate, such assodium hydroxide of sodium ethylate, is added to one mole of thebarbituric acid of Example 4 in a solvent,

such as water or alcohol, to given a solution of the alkali salt ofethyl isopropenylethylcarbinyl barbituric acid. The solution isfiltered, if necessary, and then evaporated, preferably at a low Thesolutions of the sodium salts when treated with acids regenerate thecorresponding barbituric acids. They produce an excellent hypnoticeffect when administered to the animal organism. They may be prepared inthe form of clear aqueous solutions for injection purposes.

Instead of reacting the barbituric acid in this example with an alkalinesolution of an alkali metal compound, an aqueous or other suitablesolution of ammonium hydroxide or a monoalkylamine or dialkylamine or abasic solution of an alkaline earth metal compound, such as calciumhydroxide or barium hydroxide may be reacted to give the correspondingmoncalkyl ammonium, dialkyl ammonium and alkaline earth metal salts.

propenylethylcarbinyl) malocwte A solution of sodium ethylate isprepared by adding 4.5 grams of sodium to 70 cc. of anhydrous ethylalcohol and to it is added 39.2 grams (0.196 mole) of ethylallylmalonate. With the temperature of the solution at 55-60", 23 grams(0.23 mole) of isopropenylethycarbinyl chloride is added in smallportions, shaking after each portion is added. Salt separates from thesolution immediately after a small amount of the halide has been added.The mixture is allowed to stand at room temperature for one-half hour,then 35 cc. of alcohol is slowly distilled from the solution. Thereaction mixture becomes very viscous during the 8 hours it is heated at-110". The product is isolated by diluting with sufiicient water todissolve the precipitated solid, separating the oily layer from thewater, and extracting the aqueous solution with ether. The ether extractand the ester are combined. The ether is removed by dis- I tillation andthe residue distilled under reduced pressure. Ethyl allyl-(isopropenylethylcarbinyl) malonate is a colorless liquid distilling at132- l32.5 under 4 mm. pressure for which was found to be 1.4555.

The reactions in this example may be represented as follows:

C O O CgHs CH3 CH2=CHCH2CH +CH2=C-CHCH2CH3 C O O C2115 C1 CH2=CHCH2 CH3C O O C2115 CH2=( ;CH-C

GE -CH2 00002115 EXAMPLE 7.-Prepamtion of allyl isopmpenylethylcarbinylbarbituric acid To a solution of sodium ethylate made by dissolving 3.5grams (0.15 mole) of sodium in 54 cc. of anhydrous alcohol in a cc.round-bottom flask, 14 grams (0.05 mole) of ethyl allylisopropenylethylcarbinyl malonate and 4.7 grams (0.075 mole) of urea areintroduced and the mixture heated to boiling. Twenty-seven cc. ofalcohol is removed from the solution by distillation, then the mixtureis refluxed for 4.3 hours. The product is dissolved in water andfiltered until clear. On acidification with dilute hydrochloric acid anoil separates which slowly solidifies while standing for 18-26 hours inan ice box. Purification is done by crystallization from aqueous alcoholfollowed by several recrystallizations from a benzene-petroleum ethermixture. Allyl isopropenylethylcarbinyl barbituric acid is secured as aWhite crystalline solid melting at 107-1105".

The barbituric acid of this example may be represented by the formula:

EXAMPLE 8.Preparatz'on of salts of allyl isopropcnylethylcarbinylbarbituric acid A solution containing a mole of alkali metal hydroxideor alcoholate, such as sodium hydroxide or sodium ethylate, is added toone mole of the barbituric acid of Example 4 in a solvent, such as Wateror alcohol, to give a solution of the alkali salt of allylisopropenylethylcarbinyl barbituric acid. The solution is filtered, ifnecessary, and then evaporated, preferably at a low temperature andunder diminished pressure, until the salt is obtained in solid form.

The alkali metal salts, such as the sodium salt, are white solidssoluble in water and alcohol and insoluble in water immiscible solvents.The solutions of the sodium salts when treated with acids regenerate thecorresponding barbituric acids. They produce an excellent hypnoticefiect when administered to the animal organism. They may be prepared inthe form of clear aqueous solutions for injection purposes.

Instead of reacting the barbituric acid in this example with an alkalinesolution of an alkali metal compound, an aqueous or other suitablesolution of ammonium hydroxide or a monoalkylamine or dialkylamine or abasic solution of an alkaline earth metal compound, such as calciumhydroxide or barium hydroxide may be reacted'to give the correspondingmonoalkyl ammonium, dialkyl ammonium and alkaline earth metal salts.

Although the above examples illustrate the invention, it is not limitedto the specific compounds or conditions or reactions described therein,since other compounds embodied in the formulas given may be utilized andprepared, and the other reactions or methods of preparation mentioned inthe description above can be made use of.

Some of the barbituric acids of the invention are as follows: Methylisopropenylethylcarbinyl barbituric acid, n-propylisopropenylethylcarbinyl barbituric acid, isopropylisopropenylethylcarbinyl barbituric acid, butyl isopropenylethylcarbinylbarbituric acid, amyl isopropenylethylcarbinyl barbituric acid, isoamylisopropenylethylcarbinyl barbituric acid, l-methyl-butylisopropenylethylcarbinyl barbituric acid, hexyl isopropenylethylcarbinylbarbituric acid, Z-methyl amyl isopropenylethylcarbinyl barbituric acid,ethyl isopropenylmethylcarbinyl barbituric acid, allylisopropenylmethylcarbinyl barbituric acid, ethylisopropenylallylcarbinyl barbituric acid, allyl isopropenylallylcarbinylbarbituric acid, amyl isopropenylamylcarbinyl barbituric acid, hexylisopropenylhexylcarbinyl barbituric acid, phenylisopropenylethylcarbinyl barbituric acid, phenylisopropenylphenylcarbinyl barbituric acid, ethylisopropenylphenylcarbinyl barbituric acid,

allyl isopropenylphenylcarbinyl barbituric acid,

oyclohexyl isopropenylethylcarbinyl barbituric acid, cyclopentenylisopropenylethylcarbinyl barbituric acid, cyclohexenylisopropenylethylcarbinyl barbituric acid and di-isopropenylethylcarbinylbarbituric acid.

The salts, for example the sodium salts, of each of the barbituric acidcompounds given in the last paragraph above may be readily prepared, forinstance as illustrated in Examples 5 and 8.

Inaddition to the new barbiturates, the inter- Y mediate malonic estersillustrated by Formula VI and in the examples constitute a new class ofchemical substances of value.

What I claim as my invention is: 1. A barbiturate represented by theformula,

R1 C0-NI1 where R and R1 represent hydrocarbon radicals containing notmore than six carbon atoms.

3. A barbiturate represented by the formula,

where R and R1 represent alkyl radicals containing not more than sixcarbon atoms and M represents a member of the group hydrogen, an alkalimetal, an equivalent of an alkaline earth metal, ammonium, alkylammoniumand dialkylammonium.

4. A barbituric acid represented by the formula,

CHz=O-CH CO-NH Rx CO-NH Where R and R1 represent alkyl radicalscontaining not more than six carbon atoms.

5. A barbiturate represented by the formula,

CH3 1'! CH:=CCH CO-NH o oo R1 C0-NM where R is a hydrocarbon radicalcontaining not more than six carbon atoms, R1 is a member of the groupethyl and allyl radicals and M is a member of the group hydrogen, analkali metal, an equivalent of an alkaline earth metal, ammonium,alkylarnmonium and dialkylammonium. 6. A barbituric acid represented bythe for mula,

where R is a hydrocarbon radical containing not more than six carbonatoms and R1 is a member of the group ethyl and allyl radicals.

7. A barbiturate compound of formula,

where R1 represents a member of the group ethyl and allyl radicals and Mrepresents a member of the group hydrogen, an alkali metal, anequivalent of an alkaline earth metal, ammonium, alkylammo-nium anddialkylammonium.

8. A barbituric acid of formula,

where R1 represents a member of the group ethyl and allyl radicals.

9. A barbiturate of formula,

OH: 02115 CHz=C-OE /CO-NH CIH6/ OO-Nl\ /I where M is a member of thegroup hydrogen, an alkali metal, an equivalent of an alkaline earthmetal, ammonium, alkylammonium and vdialkylammonium.

10. A barbiturate of formula,

. c 0H=oHo2 o 0-N having a melting-point of about l0'7-ll0.5 C.

13. Sodium ethyl isopropenylethylcarbinyl barbiturate which has theformula,

CH2 CzHa CHz=C-CH (JO-NH and which has hypnotic properties.

WILLIAM G. BY WATER.

